Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood-brain barrier in cerebral malaria
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Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood-brain barrier in cerebral malaria. / Adams, Yvonne; Olsen, Rebecca W; Bengtsson, Anja; Dalgaard, Nanna; Zdioruk, Mykola; Satpathi, Sanghamitra; Behera, Prativa K; Sahu, Praveen K; Lawler, Sean E; Qvortrup, Klaus; Wassmer, Samuel C; Jensen, Anja T R.
I: The Journal of Experimental Medicine, Bind 218, Nr. 3, e20201266, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood-brain barrier in cerebral malaria
AU - Adams, Yvonne
AU - Olsen, Rebecca W
AU - Bengtsson, Anja
AU - Dalgaard, Nanna
AU - Zdioruk, Mykola
AU - Satpathi, Sanghamitra
AU - Behera, Prativa K
AU - Sahu, Praveen K
AU - Lawler, Sean E
AU - Qvortrup, Klaus
AU - Wassmer, Samuel C
AU - Jensen, Anja T R
N1 - © 2021 Adams et al.
PY - 2021
Y1 - 2021
N2 - Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum-infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)- and endothelial protein C receptor (EPCR)-binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood-brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1-dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.
AB - Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum-infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)- and endothelial protein C receptor (EPCR)-binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood-brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1-dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.
U2 - 10.1084/jem.20201266
DO - 10.1084/jem.20201266
M3 - Journal article
C2 - 33492344
VL - 218
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
SN - 0022-1007
IS - 3
M1 - e20201266
ER -
ID: 255733424